ANABOLIC FUNCTION OF KREBS CYCLE

2

2

Fatty acids

Amino acids G

lucose

Glucose

Heme

Fatty acids

Glucose

Amino acids

• Role of the citric acid cycle in anabolism. • Besides its role in the oxidative catabolism of

carbohydrates, fatty acids, and amino acids, the citric acid cycle can act in synthesis, as well as in breakdown.

• It can provide precursors for many biosynthetic pathways.

• Intermediates of the citric acid cycle are drawn off as precursors in many biosynthetic pathways.

• Some of the organic acids, which are intermediates in the citric acid cycle, are the precursors for the synthesis of other molecules

• For example, in the liver intermediates from the TCA cycle are continuously withdrawn into pathways of fatty acid synthesis, amino acid synthesis, gluconeogenesis and heme synthesis.

Citric acid cycle intermediates are always in flux

• Intermediates are removed for

• biosynthesis in…..

• amphibolicamphibolic reactions =• removal of

intermediates.•  

Diagram of the citric acid cycle, indicating positions at which intermediates are drawn off for use in anabolic pathways (red arrows) Several intermediates of the cycle may serve other functions:

• Citrate may leave the mitochondria (via the citrate shuttle) to deliver acetyl-CoA into the cytoplasm for fatty acid synthesis.

– Biosynthesis of fatty acids and cholesterol.

– Citrate + ATP + CoA Acetyl CoA + OAA + ADP + Pi

Fatty acid biosynthesis

Cataplerosis of Citrate via citrate shuttle

Acetyl-CoA

Oxaloacetate

Malonyl CoA

Fatty Acids

• Acetyl-CoA is a major building block for long-chain fatty acid synthesis.

• Since pyruvate dehydrogenase is a mitochondrial enzyme and the enzymes needed for fatty acid biosynthesis are extramitrochondrial, the acetyl-CoA is recovered as citrate, cleaved back to acetyl-CoA in the cytosol by ATP-citrate lyase. (this incvolves the citrate shuttle, and is the precursor to fatty acid synthesis ).

Overview of Cholesterol biosynthesis

• alpha-ketoglutarate can serve as precursor for glutamate by simple transamination. Glutamate can then act as precursor for other amino acids and purine nucleotides.

• In the brain, alpha-ketoglutarate is converted to glutamate and GABA, both important neurotransmitters.

• Succinyl-CoA is a high-energy intermediate that can be used for heme synthesis and to activate ketone bodies in extrahepatic tissues.

• Succinyl-CoA is a central intermediate of heme groups.

•

• Succinyl CoA is used in the biosynthesis of heme The citric acid cycle intermediate succinyl CoA condenses with glycine in the mitochondrion to form -ALA (-aminolevulinic acid in the first (also the rate-limiting and the most highly regulated) reaction in the heme biosynthetic pathway.

• Succinate dehydrogenase catalyzes formation of fumarate from succinate in the Krebs cycle in a catabolic reaction.

• This reaction connects the Krebs cycle to the urea cycle or Krebs-Hanseleit cycle, which is an anabolic process, as the fumarate formed in the catabolic mode of the Krebs cycle may be used in the anabolic synthesis of urea in the urea cycle.

• These two cycles are referred to as the Krebs bicycle.

Urea Cycle

• Malate can leave the mitochondria (via the malate shuttle) for gluconeogenesis.

•

Cataplerosis of Malate via malate shuttle

Malate

Oxaloacetate

Phosphoenolpyruvate (PEP)

• Pyruvate, oxaloacetate, and alpha-ketoglutarate can be transaminated (have an amino group added) to form the amino acids alanine, aspartate, and glutamate

• Transamination of pyruvate yields alanine. • Transamination of oxaloacetate yields aspartate. • Oxaloacetate can be converted to glucose in

gluconeogenesis.• Oxaloacetate can serves as precursors for aspartate,

by simple transamination, and the aspartate can act as precursors for other amino acids and nucleotides – oxaloacetate to aspartate– oxaloacetate to PEP---aromatic A.A., formation of 3-PG.,

gluconeogenesis

• Transamination of alpha ketoglutarate yields glutamate.

gluconeogenesis

glucose

Oxaloacetate is the starting material for glucogneonesis

Several biosynthetic pathways utilize the citric acid cycle intermediates as starting materials (anabolism).

Pathways that utilize citric acid cycle intermediates include.

(1) Glucose biosynthesis (gluconeogenesis)(2) Lipid biosynthesis (Lipid anabolism )(3) Amino acid biosynthesis(4) Porphyrin biosynthesis

Summary of amphibolic pathways• Fatty acid biosynthesis• citrate acetyl CoA and oxaloacetate• acetyl CoA can build fatty acids• Heme biosynthesis• succinyl CoA + glycine porphyrins• Transaminases• oxaloacetate Aspartate-ketoglutarate Glutamate• pyruvate Alanine

TCA Cycle: It ain’t just ATP.

TCA Cycle provides intermediates for many biosynthetic processes

• As intermediates are removed to serve as biosynthetic precursors, they are replenished by anaplerotic reactions.

• Under normal circumstances, removal and replenishment are in dynamic balance so intermediates stay almost constant.

• Thus it is that ……………. citric acid cycle intermediates are always in flux